-
Inflammopharmacology Feb 2024Diabetic nephropathy (DN) is reported as one of the most serious microvascular diabetic complications and the trigger of end-stage renal disease (ESRD), underscoring the...
Diabetic nephropathy (DN) is reported as one of the most serious microvascular diabetic complications and the trigger of end-stage renal disease (ESRD), underscoring the concern of any therapeutic intervention directed at ameliorating the development and progression of DN. The current study explored the renoprotective impact of montelukast (Mon) against streptozotocin (STZ)-induced DN in rats compared to a standard anti-hyperglycemic insulin (Ins) treatment. Diabetes was induced by a single dose of STZ (55 mg/kg). Diabetic rats were treated with Mon (10 and 20 mg/kg, oral gavage) for eight weeks. Mon administration for 8 weeks after induction of diabetes conferred significant dose-dependent renoprotection, independent of blood glucose levels (unlike Ins), as evidenced by the improvement in serum creatinine, and blood urea nitrogen (BUN), and ameliorated STZ-induced renal necrotic, inflammatory alterations, and renal fibrosis. Additionally, Mon treatment in diabetic rats significantly restored redox hemostasis as evidenced by malondialdehyde (MDA) and total antioxidant capacity (TAC) levels; significantly reduced the renal expression of high mobility group box (HMGB) 1, toll-like receptor (TLR) 4, nuclear factor kappa B (NF-κB) (in the nucleus), NOD-like receptor family pyrin domain containing (NLRP) 3, and interleukin (IL)-1β. Moreover, Mon administration ameliorated the dysregulation in autophagy as evidenced by p62 and microtubule-associated protein 1A/1B-light chain 3 (LC3)-II levels. In conclusion, the renoprotective effect of Mon is potentially associated with its modulatory effect on inflammatory cytokines, antioxidant properties, and autophagy.
Topics: Animals; Rats; Inflammasomes; NLR Family, Pyrin Domain-Containing 3 Protein; Diabetic Nephropathies; NF-kappa B; Streptozocin; HMGB1 Protein; Antioxidants; Diabetes Mellitus, Experimental; Toll-Like Receptor 4; Insulin; Acetates; Cyclopropanes; Quinolines; Sulfides
PubMed: 37498374
DOI: 10.1007/s10787-023-01301-1 -
Medical Journal of the Islamic Republic... 2023NSAID-exacerbated respiratory disease (N-ERD) is a highly heterogeneous disorder with various clinical symptoms. The aspirin challenge test is a gold standard method for...
Investigation of the Relationship between Aspirin-Sensitivity and Poor Response to Medical Management in NSAIDs-exacerbated Respiratory Disease Patients with Sinonasal Polyposis.
BACKGROUND
NSAID-exacerbated respiratory disease (N-ERD) is a highly heterogeneous disorder with various clinical symptoms. The aspirin challenge test is a gold standard method for its diagnosis, and there are still no reliable in vitro diagnostic biomarkers yet. Oral challenge tests are time-consuming and may be associated with a risk of severe systemic reactions. This study aimed to evaluate whether patients with poor responses to medical management are more susceptible to being aspirin-sensitive.
METHODS
In this cohort study, after CT scanning of all patients and subject selection, conventional medical treatment was started as follows and continued for three consecutive months: at first, saline nose wash twice per day, intranasal beclomethasone spray one puff in each nostril twice per day, montelukast 10 mg tablet once daily, a ten-day course of oral prednisolone starting with the dose of 25 mg per day and taper and discontinued thereafter. Sinonasal outcome test 22 (SNOT22) was used for the evaluation of symptom severity. Statistical analyses were performed with SPSS version 23, and data were analyzed using an independent samples T-test, paired T-test, and Receiver operating curve analysis.
RESULTS
25 males and 53 females were enrolled in this study, with an average age of 41.56 ± 11.74 years old (18-36). Aspirin challenge test results were positive in 29 (37.2%) patients. The average SNOT22 scores before the treatment were 52.97 ± 17.73 and 47.04 ± 18.30 in aspirin-sensitive and aspirin-tolerant patients, respectively, and decreased to 27.41 ± 16.61 and 24.88 ± 16.72 in aspirin-sensitive and aspirin-tolerant patients after the treatment, respectively. There was no significant difference in SNOT22 scores between the groups.
CONCLUSION
The severity of symptoms before treatment and clinical improvement after treatment are not good predictors of N-ERD.
PubMed: 37457420
DOI: 10.47176/mjiri.37.63 -
Frontiers in Pharmacology 2023
PubMed: 37342595
DOI: 10.3389/fphar.2023.1223761 -
Cell Communication and Signaling : CCS Jun 2023Immunotherapy targeting programmed death-ligand 1 (PD-L1) or PD-1 in solid tumors has been shown to be clinically beneficial. However, in colorectal cancer (CRC), only a...
Immunotherapy targeting programmed death-ligand 1 (PD-L1) or PD-1 in solid tumors has been shown to be clinically beneficial. However, in colorectal cancer (CRC), only a subset of patients benefit from PD-1/PD-L1 treatment. Previously, we showed that high cysteinyl leukotriene receptor 1 (CysLTR) levels are associated with poor prognosis in CRC patients. Recently, we have revealed the role of the tumor promoter CysLTR in drug resistance and stemness in colon cancer (CC) cells. Here, we show the role of the CysLTR/Wnt/β-catenin signaling axis in the regulation of PD-L1 using both in vitro and in vivo preclinical model systems. Interestingly, we found that both endogenous and IFNγ-induced PD-L1 expression in CC cells is mediated through upregulation of CysLTR, which enhances Wnt/β-catenin signaling. Therapeutic targeting of CysLTR with its antagonist montelukast (Mo), as well as CRISPR/Cas9-mediated or doxycycline-inducible functional absence of CysLTR, negatively regulated PD-L1 expression in CC cells. Interestingly, an anti-PD-L1 neutralizing antibody exhibited stronger effects together with the CysLTR antagonist in cells (Apc or CTNNB1) with either endogenous or IFNγ-induced PD-L1 expression. Additionally, mice treated with Mo showed depletion of PD-L1 mRNA and protein. Moreover, in CC cells with combined treatment of a Wnt inhibitor and an anti-PD-L1 antibody was effective only in β-catenin-dependent (APC) context. Finally, analysis of public dataset showed positive correlations between the PD-L1 and CysLTR mRNA levels. These results elucidate a previously underappreciated CysLTR/Wnt/β-catenin signaling pathway in the context of PD-L1 inhibition in CC, which might be considered for improving the efficacy of anti-PD-L1 therapy in CC patients. Video Abstract.
Topics: Animals; Mice; Carcinogens; Programmed Cell Death 1 Receptor; Wnt Signaling Pathway; beta Catenin; Colonic Neoplasms
PubMed: 37316937
DOI: 10.1186/s12964-023-01157-6 -
Research Square May 2023Prediction of high-risk events amongst patients with mental disorders is critical for personalized interventions. In our previous study, we developed a deep...
DeepBiomarker2: Prediction of alcohol and substance use disorder risk in post-traumatic stress disorder patients using electronic medical records and multiple social determinants of health.
INTRODUCTION
Prediction of high-risk events amongst patients with mental disorders is critical for personalized interventions. In our previous study, we developed a deep learning-based model, DeepBiomarker by utilizing electronic medical records (EMR) to predict the outcomes of patients with suicide-related events in post-traumatic stress disorder (PTSD) patients.
METHODS
We improved our deep learning model to develop DeepBiomarker2 through data integration of multimodal information: lab tests, medication use, diagnosis, and social determinants of health (SDoH) parameters (both individual and neighborhood level) from EMR data for outcome prediction. We further refined our contribution analysis for identifying key factors. We applied DeepBiomarker2 to analyze EMR data of 38,807 patients from University of Pittsburgh Medical Center diagnosed with PTSD to determine their risk of developing alcohol and substance use disorder (ASUD).
RESULTS
DeepBiomarker2 predicted whether a PTSD patient will have a diagnosis of ASUD within the following 3 months with a c-statistic (receiver operating characteristic AUC) of 0·93. We used contribution analysis technology to identify key lab tests, medication use and diagnosis for ASUD prediction. These identified factors imply that the regulation of the energy metabolism, blood circulation, inflammation, and microbiome is involved in shaping the pathophysiological pathways promoting ASUD risks in PTSD patients. Our study found protective medications such as oxybutynin, magnesium oxide, clindamycin, cetirizine, montelukast and venlafaxine all have a potential to reduce risk of ASUDs.
DISCUSSION
DeepBiomarker2 can predict ASUD risk with high accuracy and can further identify potential risk factors along with medications with beneficial effects. We believe that our approach will help in personalized interventions of PTSD for a variety of clinical scenarios.
PubMed: 37292589
DOI: 10.21203/rs.3.rs-2949487/v1 -
Signal Transduction and Targeted Therapy Jun 2023The coronavirus disease 2019 (COVID-19) caused by coronavirus SARS-CoV-2 infection has become a global pandemic due to the high viral transmissibility and pathogenesis,... (Review)
Review
The coronavirus disease 2019 (COVID-19) caused by coronavirus SARS-CoV-2 infection has become a global pandemic due to the high viral transmissibility and pathogenesis, bringing enormous burden to our society. Most patients infected by SARS-CoV-2 are asymptomatic or have mild symptoms. Although only a small proportion of patients progressed to severe COVID-19 with symptoms including acute respiratory distress syndrome (ARDS), disseminated coagulopathy, and cardiovascular disorders, severe COVID-19 is accompanied by high mortality rates with near 7 million deaths. Nowadays, effective therapeutic patterns for severe COVID-19 are still lacking. It has been extensively reported that host metabolism plays essential roles in various physiological processes during virus infection. Many viruses manipulate host metabolism to avoid immunity, facilitate their own replication, or to initiate pathological response. Targeting the interaction between SARS-CoV-2 and host metabolism holds promise for developing therapeutic strategies. In this review, we summarize and discuss recent studies dedicated to uncovering the role of host metabolism during the life cycle of SARS-CoV-2 in aspects of entry, replication, assembly, and pathogenesis with an emphasis on glucose metabolism and lipid metabolism. Microbiota and long COVID-19 are also discussed. Ultimately, we recapitulate metabolism-modulating drugs repurposed for COVID-19 including statins, ASM inhibitors, NSAIDs, Montelukast, omega-3 fatty acids, 2-DG, and metformin.
Topics: Humans; COVID-19; SARS-CoV-2; Post-Acute COVID-19 Syndrome; Lipid Metabolism
PubMed: 37286535
DOI: 10.1038/s41392-023-01510-8 -
Indian Journal of Otolaryngology and... Jun 2023Adenoid Hypertrophy (AH) results in symptoms ranging from mild nasal obstruction to the dangerous obstructive sleep apnoea. Normally for such patients Adenoidectomy...
Adenoid Hypertrophy (AH) results in symptoms ranging from mild nasal obstruction to the dangerous obstructive sleep apnoea. Normally for such patients Adenoidectomy with or without Tonsillectomy is carried out. However complications like haemorrhage and recurrence of adenoid tissue are common. Thus, non-surgical therapies have attracted considerable attention as an alternative strategy. The present study is aimed at evaluating the effect of oral Montelukast, a cysteinyl- leukotriene receptor antagonist, in children with AH. Sixty children aged between 6 and 12 years with adenoid hypertrophy were randomly divided into two groups of thirty each. The study group was prescribed Tablet Montelukast 5 mg daily for 12 weeks while the control group received matching placebo. A questionnaire based upon the severity of the symptoms as well as the Adenoid Nasopharynx ratio (A/N), as measured via X-ray Adenoids and the Nasal endoscopic scores done before and after treatment (at 3 months) in the two groups were taken into consideration . The Mann Whitney Test which was used found no distinction in snoring, sleep discomfort and mouth breathing between the two groups before the start of treatment. But a significant difference was indeed observed between the two groups after treatment in case of snoring ( < 0.006), sleep discomfort( < 0.001) and mouth breathing ( < 0.001). Oral Montelukast therapy is seen to be effective not only in the reduction of the size of adenoids but also in improvement of the overall symptoms and can thus be considered as a viable alternative .
PubMed: 37275091
DOI: 10.1007/s12070-022-03167-1 -
American Journal of Physiology. Lung... Aug 2023Asthma is one of the most common noncommunicable diseases in the world. Approximately 30% of severe cases are associated with fungal sensitization, often associated with...
Asthma is one of the most common noncommunicable diseases in the world. Approximately 30% of severe cases are associated with fungal sensitization, often associated with allergy to the opportunistic mold . Leukotrienes, immunopathogenic mediators derived from the metabolism of arachidonic acid (AA) by 5-lipoxygenase (5-LOX), are often elevated in severe asthma. As such, these mediators are Food and Drug Administration-approved therapeutic targets of the antiasthmatic drugs Zileuton/Zyflo and Singulair/Montelukast. A second enzyme involved in AA metabolism is 12/15-lipoxygenase (12/15-LOX; ). Here, C57BL/6 wild-type (WT) mice subjected to experimental fungal asthma had increased expression of mRNA and increased levels of 12-HETE, a product of 12/15-LOX activity, in the lung when compared with naïve and vehicle-treated mice. Mice deficient in 12/15-LOX () demonstrated better lung function, as measured by airway hyperresponsiveness (AHR), during fungal asthma. Histological assessment revealed reduced inflammation in the lungs of mice compared with WT mice, which was corroborated by flow cytometric analysis of multiple myeloid (eosinophils and neutrophils) and lymphoid (CD4+ T and γδ T) cell populations. This was further supported by decreased levels of specific chemokines that promote the recruitment of these cells. Likewise, type 1 and 2, but not type 17 cytokines, were significantly lower in the lungs of mice. Bone marrow chimera studies revealed that the presence of 12/15-LOX in hematopoietic cells contributed to AHR during fungal asthma. Taken together, our data support the hypothesis that hematopoietic-associated 12/15-LOX contributes to type 1 and 2 responses and exacerbation of allergic fungal asthma. Humans with asthma sensitized to fungi often have more severe asthma than those who are not sensitized to fungi. Products of arachidonic acid generated via 5-lipoxygenase are often elevated in severe asthma and are successful FDA-approved drug targets. Less understood is the role of products generated via 12/15-lipoxygenase. We demonstrate that 12/15-lipoxygenase expression in hematopoietic cells contributes to type 1 and 2 responses and impaired lung function during allergic fungal asthma.
Topics: Animals; Humans; Mice; Arachidonate 15-Lipoxygenase; Arachidonate 5-Lipoxygenase; Arachidonic Acid; Asthma; Disease Models, Animal; Mice, Inbred C57BL; Mice, Knockout
PubMed: 37253655
DOI: 10.1152/ajplung.00090.2023 -
Pharmaceuticals (Basel, Switzerland) May 2023Self-inflicted violence is a major and growing public health problem and its prediction and prevention is challenging for healthcare systems worldwide. Our aim was to...
Self-inflicted violence is a major and growing public health problem and its prediction and prevention is challenging for healthcare systems worldwide. Our aim was to identify prescribed drugs associated with self-directed violent behaviors in Spain. A descriptive, longitudinal and retrospective study of spontaneous reports of adverse drug reactions corresponding to self-directed violence was recorded in the Spanish Pharmacovigilance Database (FEDRA) from 1984 to 31 March 2021. A total of 710 cases were reported in the study period. The mean age was 45.52 years (range 1-94). There were no gender differences except in children, where most reports were of male children. The main therapeutic groups that were involved included drugs for the nervous system (64.5%) and anti-infectives for systemic use (13.2%). The most commonly reported drugs were varenicline, fluoxetine, lorazepam, escitalopram, venlafaxine, veralipride, pregabalin, roflumilast and bupropion. There were reports of montelukast, hydroxychloroquine, isotretinoin, methylphenidate, infliximab, natalizumab, ribavirin and efavirenz, which were less known to be involved in self-directed violence. This study shows that self-directed violence is a rare adverse drug reaction, and can be related to the use of some medicines. It is important for healthcare professionals to consider this risk in their clinical praxis, implementing person-centred approaches. Further studies are needed, considering comorbidities and potential interactions.
PubMed: 37242555
DOI: 10.3390/ph16050772